Allosteric Mechanism of Human Mitochondrial Phenylalanyl-tRNA Synthetase: An Atomistic MD Simulation and a Mutual Information-Based Network Study.

Aminoacyl-tRNA synthetases (aaRSs), a family of ubiquitous and essential enzymes, can bind target tRNAs and catalyze the aminoacylation reaction in genetic code translation. In this work, we explore the dynamic properties and allosteric communication of human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS) in free and bound states to understand the mechanisms of its tRNAPhe recognition and allostery using molecular dynamics simulations combined with the torsional mutual information-based network model. Our results reveal that hmPheRS's residue mobility and inter-residue motional coupling are significantly enhanced by tRNAPhe binding, and there occurs a strong allosteric communication which is critical for the aminoacylation reaction, suggesting the vital role of tRNAPhe binding in the enzyme's function. The identified signaling pathways mainly make the connections between the anticodon binding domain (ABD) and catalytic domain (CAD), as well as within the CAD composed of many functional fragments and active sites, revealing the co-regulation role of them to act coordinately and achieve hmPheRS's aminoacylation function. Besides, several key residues along the communication pathways are identified to be involved in mediating the coordinated coupling between anticodon recognition at the ABD and activation process at the CAD, showing their pivotal role in the allosteric network, which are well consistent with the experimental observation. This study sheds light on the allosteric communication mechanism in hmPheRS and can provide important information for the structure-based drug design targeting aaRSs.